Injection molding process for the preparation of an oral delivery device for a pharmaceutically active agent

ABSTRACT

An injection moulding process for the preparation of an oral delivery device comprising a core which contains a pharmaceutically active agent, having a coating with one or more openings leading to such a core. The invention also relates to devices produced by the process, and to injection moulds suitable for performing the process.

[0001] The present invention relates to a novel process for thepreparation of an oral delivery device for a pharmaceutically activeagent. In particular, the invention relates to a process for thepreparation of an oral delivery device comprising a core which containsthe active agent, having a coating with one or more openings leading tosuch a core. The invention also relates to novel oral delivery devicesobtainable by the process of this invention.

[0002] The coating of tablet cores comprising an active agent, forexample to prepare a pharmaceutical tablet for oral administration, iswell established practice. The common reasons for so doing include:improved product mechanical integrity; improved stability to thesurrounding environment (particularly air, moisture and light); a meansof modifying the release rate of the active agent; and in order toachieve distinctive or improved aesthetic characteristics. Processes forcoating are also well established in the art.

[0003] Of the factors described above, the use of a coating to controlthe rate of release of an active agent has received considerableattention and, indeed, many different devices have been developed forsuch a purpose. Some of the devices utilised are discussed in U.S. Pat.No. 5,004,614. This patent describes a controlled release device with animpermeable coating having an orifice for release of drug when thedevice has been orally administered and is immersed in an aqueous mediumsuch as gastro-intestinal fluid. Such devices are prepared eitheraccording to pressure coating or dip coating methods and the orifice isformed by removing sections of the formed coating with laser ormechanical drilling techniques.

[0004] It is an object of this invention to provide an alternativeprocess for the preparation of devices of the above described type. Itis a particular object of this invention to provide an improved processfor the manufacture of devices of the type disclosed in U.S. Pat. No.5,004,614, the contents of which are incorporated herein by reference.It is also an object of the invention to provide novel constructions ofdevices of this general type. Other objects and advantages of theinvention will become apparent from the following description.

[0005] The present invention therefore provides, in a first aspect, aprocess for the preparation of a delivery device comprising a core whichincludes a pharmaceutically active agent covered by an outer coatingwhich includes one or more openings communicating from the exterior ofthe device to the core characterised in that the outer coating isapplied by injection moulding said coating around said core.

[0006] A process for making a device according to this invention may,for example, comprise the steps of:

[0007] providing, if necessary preparing, the core of the devicecomprising a pharmaceutically active agent;

[0008] locating said core within a mould cavity surrounding the core,said mould cavity defining the required dimensions of the outer coatingand preferably also defining the required position, shape and dimensionsof the one or more openings;

[0009] injecting a fluid mouldable material into said mould cavity;

[0010] allowing the material to set to thereby form the outer coating;

[0011] separating the formed device from the mould cavity.

[0012] The core may be prepared by compressing suitable ingredients forthe core to form a compacted mass which comprises the core of the device(also referred to herein as “tablet core”). This may be prepared usingconventional tablet excipients and formulation compression methods.Thus, the core would typically comprise the active agent or agents alongwith excipients that impart satisfactory processing and compressioncharacteristics such as diluents, binders and lubricants. Additionalexcipients that may form part of the core of the device includedisintegrants, flavourants, colorants and release modifying agents.Typically the active agent and excipients are thoroughly mixed prior tocompression into a solid core. The core of the device can be formed byconventional tablet-forming processes such as wet granulation methods,dry granulation methods or by direct compression. The core can beproduced according to any desired pre-selected shape such as bi-convex,hemi-spherical, near hemi-spherical, round, oval, generally ellipsoidal,oblong, generally cylindrical or polyhedral, e.g. a triangular prismshape.

[0013] A preferred shape of core is one which is generally ofcylindrical shape having two opposite facing generally convex circularend faces. Such convex end faces may be of a generally part-sphericaldomed convex shape, or generally conical or frustro conical. Anotherpreferred shape of core is a convex or of a bi-convex shape comprisingtwo opposite-facing domed surfaces which are generally circular orelliptical in plan.

[0014] The term “near hemi-spherical” is intended to be construed in themanner described in U.S. Pat. No. 5,004,614. The term “cylindrical” isintended to include both true cylindrical shapes and distortedcylindrical shapes. Preferably the core is formulated into a bi-convexshape, e.g. having two domed opposite surfaces. If the core has corners,e.g. corners between cylindrical side surfaces and convex end surfaces,a rounded corner radius of ca. 1 mm is preferred to assist flow of thefluid coating material during injection.

[0015] The core could be produced in a multi-layered (e.g. bi- or tri-layered) form.

[0016] The delivery device of the invention is most suitable as an oraldelivery device, as it can conveniently be made in the shape and size ofa pharmaceutical tablet, well known to those acquainted withpharmaceutical technology. The core can comprise active agents which aresuitable for use in a wide range of therapies, particularly for oraldelivery, and include those listed U.S. Pat. No. 5,004,614. The quantityof active agent present within the core is a matter to be determinedbased upon typical pharmaceutical considerations, e.g. known dosages forthe active materials contained therein, and is not limited by theprocess of this invention or the structure of the delivery devicesformed thereby.

[0017] It will be appreciated that to carry out the process of thisinvention, the tablet core must be accurately located within the mouldcavity to thereby achieve a precisely defined thickness of coatingand/or positioning of the one or more opening. Preferably the tabletcore is located via robotic means.

[0018] The core of the device is coated with a suitable material by aninjection moulding process. Injection moulding generally involves theinjection of a molten thermoplastic, fluid-like material, often a fluidpolymer under pressure and usually at an elevated temperature, into aprecisely made die cavity in a mould block. Upon cooling, typically toambient temperature, the fluid material solidifies to form a solidproduct reproducing the internal shape of the cavity. Alternatively theinjection moulding process may use a thermosetting fluid-like material,for example injecting the material in a fluid state into a heated mould,where the heat acts upon the thermosetting material to solidify it.Silicone materials are known thermosetting materials. Such mouldingtechniques are well known in the art of manufacture of small plasticmaterial components. Typical injection moulding apparatus comprise apolymer feed system, consisting of a polymer reservoir, e.g. a hopper ofpolymer pellets or granules, a heater and a screw pump that forces thefluid polymer down an injection port towards the mould.

[0019] The injection moulding process of this invention can be carriedout on a standard injection moulder, e.g. of a hot or cold runner type.A hot runner system is preferred, and although valve gates could be usedto eliminate the gate pip, in practice the very small residual gate pipleft by conventional hot runner machines is likely to be insignificant.Such apparatus is capable of operating over a wide range of temperaturesand pressures. It will be appreciated however, that a principal factoraffecting the utility of this invention is the capability of the tabletcore to withstand the rigours of injection moulding conditions. Forexample many pharmaceutically active agents are complex organiccompounds which are susceptible to thermal degradation at elevatedtemperatures, which may be exacerbated by simultaneous application ofhigh pressure. Therefore it is preferred to use temperatures for theinjection moulding process which are considered to minimise or ideallyavoid any thermal degradation for the active agent in question. For manysuch agents suitable processing conditions to achieve this are specifiedin the literature. For these reasons, it is believed that typicaloperational conditions would be between temperatures of 25-300° C., moretypically 50-250° C. and especially 50-150° C. Preferably the injectionmoulding pressure should be less than 6000 psi (ca. 400-450 kg/cm²) toavoid damage to a tablet core within the mould cavity, typicallypressures of 200 to 1000 psi (ca. 14-70 kg/cm²), more typically 400 to600 psi (ca. 30-45 kg/cm²) have been found suitable. Conversely thetablet core should be made of materials and using suitable conditionsthat the core can withstand such pressures within the mould withoutbreaking or crumbling.

[0020] The material of the outer coating may be any material whichblocks (either permanently of for a suitable time period) exposure ofthe core to an environmental fluid, e.g. a gastro-intestinal fluid, andis not removed by dissolution or otherwise disrupted before apredetermined duration for controlled, delayed or sustained release ofthe active material in the core has occurred. Alternatively, the coatingmaterial may be selected because of aesthetic considerations. Anypharmaceutically acceptable fluid mouldable material which exhibitsthermoplastic properties can be used as an outer coating for the tabletcore, and suitable materials include thermoplastic organic polymers.Those skilled in the art of injection moulding characterise the flowproperties of polymeric materials according to a melt flow index whichranges from 1 g/10 min (very poor flow) to 50 g/10 min (very high flow).It has been found that materials that exhibit a melt flow index in therange of 15-30 g/10 min are particularly suitable for use in thisinvention. Representative materials and their blends suitable for use asa coating material in this invention include those listed in U.S. Pat.No. 5,004,614. Preferred coating materials include the polymethacrylatecopolymers, natural waxes and lipids, and biodegradable polymers ingeneral. Other suitable polymer materials include polyvinyl acetates,such as the 40 and 20 grades thereof, cellulose acetate, butyrate andphthalate, EVA (ethylene vinyl acetate) or HPC (hydroxypropylcellulose), silicones, or copolymers of methacrylic acid,methylmethacrylate, and methyl acrylate, such as that known as 4135F,available from Röhm polymers, or a blend based on 4135F. 4135F comprisesa methacrylic acid, methylmethacrylate, methyl acrylate copolymer in atypical ratio 25:65:10 with a dissolution threshold of pH greater than7.2.

[0021] Accordingly in a further aspect, the present invention provides adevice adapted for oral delivery of a pharmaceutically active agent,when made by a process as described herein. Typically such a devicecomprises a core which includes a pharmaceutically active agent coveredby an outer coating which includes one or more openings communicatingfrom the exterior of the device to the core characterised in that theouter coating is a polymeric material exhibiting a melt flow index whichranges from 1 g/10 min (very poor flow) to 50 g/10 min (very high flow),especially that exhibits a melt flow index in the range of 15-30 g/10min, applied by injection moulding said coating around said core.

[0022] The thickness of the outer coating can be readily adapted. Fordevices such as those described in U.S. Pat. No. 5,004,614 it isimportant that, for materials that do exhibit a certain degree ofpermeability to environmental fluids, that the coating is applied atsuch a thickness to prevent exposure to the core before the desiredduration of the controlled release has passed. For immediate releasedevices a considerably thinner coating could be utilised or a coatingapplied which is designed to dissolve in gastrointestinal fluid. It isbelieved that a suitable coating thickness that can be achieved by thisprocess of this invention is the range of 0.1 mm to 2 mm, preferably inthe range 0.2 to 0.8 mm, more preferably in the range 0.1 to 0.6 mmTypically tablet cores may be made with a tolerance of ±0.025 mm on acylindrical diameter, and ±0.1 mm on a cylindrical height. Typicallythere might be variation of less than 0.03 mm in an injection mouldcavity, and these figures indicate typical tolerance ranges for thethickness of the coating achievable by the process of this invention. Animportant factor to consider is the melt flow index of the thermoplasticpolymer. Thus, to obtain the thinnest coating section it will benecessary to use a polymer with a high melt flow characteristics. Evensmall thickness variations can have significant effects on melt flow,and as a coating thickness of nominally 0.6-0.4 mm appears to be optimumfrom the point of view of the moulding process, although pharmaceuticalrequirements of the delivery device might require other thicknesses.

[0023] A mould suitable for use in the process of this invention has acavity in which the tablet core may be located with a space around thesaid core to define the required shape and dimensions of the coating,with one or more internal member extending from the interior surface ofthe mould cavity to abut the said core and to define the shape andposition of the said one or more opening. Typically the mould willincorporate plural cavities to maximise the production rate of theprocess, as is standard practice in the injection moulding art.Typically the mould might include 16 cavities. The internal membersdefine the openings of the device. Such internal members are preferablydesigned without any overhang between them and the interior surface ofthe mould cavity, so that they can be easily separated from the deviceproduced therein without any damage occurring to the coating. Theseinternal members may also serve to hold the core in place as the fluidcoating material is injected into the mould cavity.

[0024] In a preferred construction of mould, one or more internal memberis resiliently mounted, e.g. spring-mounted, so as to be able to movereciprocally resiliently inward and outward relative to the mouldcavity. By this construction such a resilient internal member can applya resilient pressure to a core when enclosed in the mould cavity to helpto hold the core in place within the mould cavity. Also the ability ofsuch a member to move slightly when it contacts a tablet core on closingthe mould can help to relieve any pressures on the core which might tendto break the core, and can help the internal member to accommodate tovariations in the size between tablet cores. Preferably the resilientmounting of such an internal member should be such as to apply aresilient pressure of up to 200 psi (ca. 14 kg/cm²) to the tablet core,or conversely to be resiliently moveable under such a pressure appliedthereto.

[0025] It is also preferred to provide an internal member with a vacuumconduit passing therethrough to the outside of the mould, by whichreduced pressure may be applied to a tablet core in contact with themember to assist in retaining the core in place in the mould. Suitablythe vacuum conduit may pass through a resiliently mounted internalmember as described above. Such a vacuum conduit may be useful both inmoulds which close along a horizontal axis such that the reducedpressure prevents the cores from falling out of the cavity, and alsomoulds which close along a vertical axis so that the reduced pressuresupplements gravity in holding the core in place.

[0026] Normally an injection mould has one fixed part and a secondmoving part which moves into contact with the fixed part to close themould. Suitably the resilient member and any vacuum conduit could be onthis fixed part.

[0027] For use with a mould as described above having an internal memberit is preferred to provide the core with at least one small seatingindentation of a shape generally corresponding to the part of the memberthat contacts the core, and so positioned on the core that when themould encloses a tablet core, the member seats in the indentation. Thiscan help to positively locate the core in the mould cavity and to securethe core in place in the mould cavity. In the above-described bi-convexcore such an indentation may be located on one or both of the convexsurfaces, e.g. the convex end surfaces of the generally cylindricalcore. Such an indentation may be need to be at most 1.5 mm deep, andpreferably for example may need to be only ca. 0.005 cm deep. Suitablysuch an indentation is tapered to be narrowest at its bottom, e.g.having a frustro-conical profile. The core may also be provided with oneor more, preferably at least three small seating projections e.g. ribs,to engage with the inner surface of the mould cavity, e.g. withcorresponding concavities therein, to assist in locating the core withinthe mould cavity. Such projections may be shaped to make only a pointcontact with the mould cavity so as to avoid resulting in the formationof any corresponding opening through the coating.

[0028] Generally the mould cavity is made in a multi-part, preferably atwo part mould construction, which close together with great precision,where each part defines a respective part of the mould cavity. Whenassembled together the two mould parts define an internal cavity i.e.such that, on closure, a cavity around the tablet core is defined whichcorresponds to the required dimensions of the coating. Such aconstruction further allows the mould cavity to be opened to allow theformed device to be separated from the mould. Moulds of this generaltype for use in injection moulding processes are well known in the art.The one or more-internal members can be located at any suitable positionon the inner wall surface of the mould cavity and are preferably madeintegral with the mould. Where a multi-part construction is utilised theinternal members may be located upon one or more mould parts. The partsof such a multi-part mould may close horizontally, i.e. along ahorizontal axis, or vertically, i.e. along a vertical axis. Ahorizontally closing mould is preferred.

[0029] The mould may also incorporate one or more pairs of retractableside cores which can move together to grip a tablet core when the corehas been located in a part of the mould, to help to hold the core inplace until the mould is fully closed. Such side cores may beparticularly useful in a horizontally closing mould.

[0030] A typical process of the invention may involve the steps (1)loading tablet cores into a feeder, e.g. a vibratory bowl feeder, fordischarge onto one or more conveyor, from which the tablet cores can becollected in the alignment required for picking up by a robot equippedwith suction grippers, (2) the robot placing the tablet cores onto aregister station to accurately position them in the spatial arrangementrequired for insertion into the mould cavities, (3) a robot picking upthe tablet cores and inserting them into the mould cavities, (4)performing the injection of coating material, (5) if a verticallyclosing mould is used, removing the completed devices from the mouldcavities using a robot. Step (2) might be eliminated, e.g. by designinga collection device at the end of the conveyor with sufficient accuracythat subsequent alignment on a register is not required. Steps (3) and(4) might be combined by designing a robot with two sets of grippers,one to hold the tablet cores and one to hold the completed articles, sowhilst the mould is open the gripper head could extract the completeddevices, index sideways, and place new tablet cores into the cavities.

[0031] The invention also provides, in a further aspect, a die or mouldsuitable for use in the moulding process, which has a cavity in which atablet core may be located and being of dimensions such as to leave aspace around the said core to define the required shape and dimensionsof the coating, with one or more internal members extending from theinterior surface of the mould cavity to abut the said core.

[0032] It will be appreciated that the required shape, size, number ofopenings and the geometric arrangement of openings required for thedevice can be readily achieved by a suitable arrangement of the shape,size, number and relative positions of the internal members(s) on themould or mould part. Any single opening can be as fine as 0.1 um and upto as large as a face of the tablet core e.g. 10 mm. Typical openingswould be in the range 0.5 mm-4 mm. Preferably, the opening(s) of thedevice will comprise about 10-60% of the total face area of the device.The opening may have any convenient shape, but is preferably rounded,e.g. substantially circular or elliptical.

[0033] For example, in one embodiment the device may comprise a corewhich is generally of cylindrical shape having two opposite facingsubstantially circular end faces or of a bi-convex shape comprising twoopposite-facing domed surfaces which are generally circular orelliptical in plan, covered with an outer coating which generallyconforms to the outer shape of the core, the coating having two oppositefacing openings therein communicating with substantially the centre ofeach of said respectively substantially circular or domed surfaces.

[0034] The injection moulding process of this invention can be used toproduce a device which can be used for immediate, delayed or sustainedrelease, for example to achieve release of the active agent at apre-determined part of the gastrointestinal tract. Those skilled in theart, when considering the release profile of a device containing anactive agent, would consider factors such as drug solubility, thesurface area and number of openings, coating thickness and the tabletcore formulation properties. It will be appreciated that such variationsin device can be readily accommodated by the process of this invention.

[0035] This process differs from known methods inter alia in that thecoating is applied to create the device in a single operation i.e. nofurther processing of the coating is required such as mechanicaldrilling of the coat to expose the core. It permits an improved methodof producing devices with a varying number, size and shape of openings.Moreover, the accuracy of opening size is more reproducible. It isbelieved that this process is more robust and simpler to operate thanknown methods and is particularly suitable for mass production of suchdevices.

[0036] The invention will now be described by way of example only withreference to the accompanying drawings.

[0037] FIGS. 1 to 3 schematically shows sequential stages in the use ofthe process to make a device in accordance with this invention.

[0038]FIGS. 4 and 5 show a device as made using the process of thisinvention.

[0039]FIG. 6 shows a preferred injection mould for the process of theinvention.

[0040]FIG. 7 shows a preferred shape of tablet core.

[0041] With respect to FIGS. 1 to 3, a tablet core 1 is shown within amould overall 2, made in two mating halves 2A and 2B. The core 1 is of agenerally cylindrical shape having two opposite facing substantiallycircular end faces and cylindrical side walls, and FIG. 1 shows thiscylindrical core in longitudinal section. The mould defines a cavity 3which defines the shape of the coating to be applied to the tablet core,each of the two halves 2A and 2B defines a part cavity so that when thetwo halves 2A and 2B are put together the entire cavity 3 is defined.The cavity 3 conforms closely to the shape and dimensions of the core 1,but leaves a gap around the core 1 which subsequently defines thethickness of the coating to be formed therein.

[0042] Extending from the inner wall of the mould cavity 3 are internalmembers being projections 4 integrally formed with the mould parts 2Aand 2B. These projections 4 abut against the core 1 when this is withinthe mould cavity 3, and serve both to hold the core in place within thecavity, preventing the core from being dislodged when coating materialis injected into the cavity, and to define the size, shape and positionof the openings to be formed in he coating. These projections 4 areshaped without any overhang between them and the inner wall of the mouldcavity, to allow the projections to be removed from the subsequentlyformed coating without damaging the coating. Suitably the projections 4may taper, being narrowest at the end remote from the inner wall of themould cavity.

[0043] In FIG. 1 the mould 2 is shown in an open configuration, with afixed mould part 2A lowermost, and the tablet core 1 resting on theprojection. In FIG. 2 the mould 2 has been closed, so that theprojection 4 of the upper mould part 2B has come into contact withtablet core 1.

[0044] In FIG. 3 a molten coating material 6 has been injected into thecavity 3 via injection port 5 positioned at a convenient point on thefixed part 2A of the mould 2. Following cooling the two mould parts 2Aand 2B are opened and the formed device 7 is ejected.

[0045] The device 7 is shown in cross section and a plan viewrespectively in FIGS. 4 and 5, and comprises the core 1, enclosed by thecoating 6, through which extend the two openings 8 corresponding to therespective positions of the two projections 4.

[0046] In FIG. 6 a preferred construction of mould 20 is shown in crosssection. This has two parts 20A, 20B corresponding to those 2A, 2B ofmould 2. These parts 2A, 2B have internal projections 24A, 24Bcorresponding to those 4 of mould 2. Each projection 24A, 24B is of afrustro conical shape, widest at its base where it meets the innersurface of the mould cavity 23. The projection 24A in the fixed part 20Ais resiliently reciprocally moveable in the direction of the arrows,under the biasing action of a spring (not shown) bearing upon its end24C outside the mould part 20A, and the projection 24A is slideablymounted in a guide channel 25 passing through the mould part 20A (theclearance in the channel 25 between the part 24A and the mould part 20Ais exaggerated for clarity). The resilient mounting of the projection24A is such as to move under a downward pressure of ca. 200 psi from atablet core (not shown) bearing thereon. Passing through projection 24Ais a vacuum conduit 26, via which a partial vacuum can be applied tosuch a tablet core resting on projection 24A downwards. There is aninjection gate 27 in the lower fixed mould part 24A for injection offluid coating material.

[0047] Referring to FIG. 7 a preferred tablet core shape 71 is shown inplan (FIG. 7A) and in side view (FIG. 7B). The shape is generallycylindrical, with a cylindrical part 72 having spherically domed convexend faces 73, 74. In each face 73, 74 is an indentation 75, 76 of aprofile each matching the convex frustro-conical profile of theprojections 24A, 24B of the mould 20. The slope of the conical sides ofthese indentations is ca 35° relative to the longitudinal cylindricalaxis of the core 71. The diameter of the outer rim of each indentation75, 76 is ca. 70-75% of the overall diameter of the cylindrical shape,and the depth in the longitudinal direction is ca. 0.4 mm.

EXAMPLE 1

[0048] The following tablet cores were formed by conventional means bymixing together the active ingredients with excipients and compressingto form the tablet core. These examples are intended to be by way ofillustration rather than limitation.

[0049] Tablet core a) represents a core that is suitable for use in animmediate release formulation which consists of 10% active ingredient,60% microcrystalline cellulose, 24% lactose, 5% starch glycolate(disintegrant) and 1% magnesium stearate (lubricant).

[0050] Tablet b) represents a core that is suitable for use in acontrolled release formulation which consists of 10% active ingredient,40% hydroxypropylmethyl cellulose (HPMC), 24% lactose, 20%microcrystalline cellulose, 5% starch glycolate and 1% magnesiumstearate.

[0051] The coating material used was a low density polyethylene producedby Exxon Chemical. The grade was LD600BA natural. This materialdemonstrates a wide range of processing temperatures (160 to 240° C.)and has a melt flow index of 20.5 g/10 min. Operating conditionsutilised were 150° C. and pressure of 400 psi.

[0052] The injection moulding machine used was a 35T Arburg.

[0053] The tablet cores shown in FIGS. 1 to 5 and 7 typically had adiameter of 8 mm. The coating had a thickness, as defined by the gap inthe cavity between the core and the inner wall of the cavity of ca. 0.5mm. The openings 7 in the coating were typically circular in shapehaving a diameter of 1 mm, or ca. 6 mm using the core shape shown inFIG. 7.

[0054] It has been found that these injection moulding operatingconditions did not have an adverse effect on the tablet core i.e.mechanical integrity was maintained.

1. A process for the preparation of a device comprising a core whichincludes a pharmaceutically active agent covered by an outer coatingwhich includes at least one opening communicating from the exterior ofthe device to the core in which the outer coating is applied byinjection molding said coating around said core.
 2. A process accordingto claim 1, which comprises; locating said core within a mold cavitysurrounding the core, said mold cavity defining the required dimensionsof the outer coating and also defining the required position, shape anddimensions of each said opening; injecting a fluid moldable materialinto said mold cavity; allowing the material to set, thereby forming theouter coating; and separating the device, comprising the core, the outercoating, and said at least one opening from the mold cavity.
 3. Aprocess according to claim 1, in which said fluid moldable material isinjected at a pressure less than 400-450 kg/cm².
 4. A process accordingto claim 2, in which the mold cavity has an interior surface, in which aspace is provided between said interior surface of the mold cavity andthe core, said space defining the required shape and dimensions of thecoating, and in which an internal member extends from the interiorsurface of the mold cavity through each said opening, to abut the saidcore and to define the shape and position of the opening through whichthe internal member extends.
 5. A process according to claim 4, in whichsaid internal member is resiliently mounted for inward and outwardmovement relative to the mold cavity.
 6. A process according to claim 5,wherein the internal member is resiliently moveable under a pressure ofnot more than 14 kg/cm³ applied thereto.
 7. A process according to claim5, wherein a reduced pressure is applied through a vacuum conduitextending through said internal member from the inside to the outside ofthe mold, and said reduced pressure is applied to said core, while thecore is in contact with the internal member, to assist in retaining thecore in place in the mold.
 8. A mold 4 for forming a device comprising acore which includes a pharmaceutically active agent covered by aninjection-molded outer coating having at least one opening communicatingfrom the exterior of the device to the core, in which the outer coatingis applied by injection molding of said coating around said core saidmold having a cavity in which said core may be located with a spacearound the said core to define the required shape and dimensions of thecoating, said mold cavity having an interior surface and at least oneinternal member extending from the interior surface of the mold cavityto abut the said core and to define the shape and position of the saidat least one opening.
 9. A mold according to claim 8, having two partswhich are separable from each other, and which come together by relativevertical movement.
 10. A device adapted for oral delivery of apharmaceutically active agent, comprising a core which includes apharmaceutically active agent part of which is covered by aninjection-molded outer coating which includes at least one openingcommunicating from the exterior of the device to the core,.
 11. A deviceaccording to claim 10, wherein the outer coating is a polymeric materialexhibiting a melt flow index in the range of 15-30 g/10 min, said outercoating being applied by injection molding said coating around saidcore.
 12. A device according to claim 10, wherein the outer coating is apolymeric material is selected from polymethacrylate copolymers, naturalwaxes and lipids, biodegradable polymers, polyvinyl acetate, celluloseacetate, butyrate and phthalate, ethylene vinyl acetate, hydroxypropylcellulose, copolymers of methacrylic acid, methylmethacrylate, methylacrylate, and silicones.
 13. A device according to claim 11, in whichthe outer coating has a thickness in the range 0.1 to 2.0 mm.
 14. Adevice according to claim 10, wherein the material of the outer coatingis in contact with said covered part of the core and blocks exposure ofsaid covered part of the core to an environmental fluid.
 15. A deviceaccording to claim 10, wherein the core has a cylindrical side wall andtwo oppositely facing, convex circular end faces.
 16. A device accordingto claim 10, wherein the core has two opposite-facing domed surfaceswhich are circular or elliptical in plan.
 17. A device according toclaim 10, wherein the outer coating conforms to the outer shape of thecore, the coating having two opposite facing openings thereincommunicating from the exterior of the device to the core.
 18. A processaccording to claim 4, wherein the core has a seating indentation of ashape corresponding to the part of said internal member of the mold thatabuts the core, and so positioned on the core that, when the moldencloses the core, the internal member seats in the indentation.
 19. Aprocess according to claim 2, wherein the core has at least one seatingprojection which engages with the mold cavity.